Platelet Phagocytosis and Processing of &bgr;-Amyloid Precursor Protein as a Mechanism of Macrophage Activation in Atherosclerosis
作者:
Guido De Meyer,
Dieter De Cleen,
Susan Cooper,
Michiel Knaapen,
Dominique Jans,
Wim Martinet,
Arnold Herman,
Hidde Bult,
Mark Kockx,
期刊:
Circulation Research: Journal of the American Heart Association
(OVID Available online 2002)
卷期:
Volume 90,
issue 11
页码: 1197-1204
ISSN:0009-7330
年代: 2002
出版商: OVID
关键词: &bgr;-amyloid peptide;amyloid precursor protein;foam cells;inducible nitric oxide synthase;nitric oxide
数据来源: OVID
摘要:
In human occluded saphenous vein grafts, we previously demonstrated cytotoxic foam cells, presumably derived from macrophages engulfing platelets. In the present study, we investigated whether platelet phagocytosis occurs in human atherosclerotic plaques, whether this activates macrophages, and whether the platelet constituent, amyloid precursor protein (APP), was involved. Immunohistochemistry documented the presence of APP, &bgr;-amyloid peptide (A&bgr;, cleaved from APP), and platelets (CD9), along with inducible NO synthase (iNOS) and cyclooxygenase-2, two markers of macrophage activation, around microvessels in advanced human carotid artery plaques (n=18). A&bgr; colocalized with iNOS-expressing macrophages that were often surrounded by platelets. In vitro, murine J774 and human THP-1 macrophages were incubated with or without washed human platelets. Coincubation of macrophages and platelets led to platelet phagocytosis (electron and confocal microscopy) and formation of lipid-, APP-, and A&bgr;-containing foam cells. These expressed iNOS mRNA (reverse transcription–polymerase chain reaction) and protein and produced nitrite and tumor necrosis factor-&agr; (ELISA). Macrophage pretreatment with 4-(2-aminoethyl)benzenesulfonyl fluoride, a protease inhibitor, reduced APP processing and inhibited NO biosynthesis induced by platelet phagocytosis but not by lipopolysaccharides. Human atherosclerotic plaques and J774 and THP-1 macrophages contained mRNA of the APP-cleaving enzyme &bgr;-secretase. This is the first demonstration of A&bgr;, a peptide extensively studied in Alzheimer’s disease, in human atherosclerotic plaques. It was present in activated iNOS-expressing perivascular macrophages that had phagocytized platelets. In vitro studies indicate that platelet phagocytosis leads to macrophage activation and suggest that platelet-derived APP is proteolytically processed to A&bgr;, resulting in iNOS induction. This represents a novel mechanism for macrophage activation in atherosclerosis.
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